2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent immunosuppressive agents known. Humans are exposed to low levels of this and related chemicals on a daily basis. Although the effects on the human immune system are not known, in experimental animals TCDD produces biological and toxic effects by binding to a gene regulatory protein, the Ah receptor (AhR), to inappropriately modulate gene expression. The exact mechanisms responsible for induced immunotoxicity are not known. A major obstacle has been the lack of understanding of the actual primary tissue and cell targets. It has been hypothesized that progenitor and/or immature bone marrow and thymic cells are direct targets for TCDD, that developmental arrest of these cells contributes to elicited immune toxicity, and that TCDD, via that AhR, alters signal events in these cells at critical stages in differentiation. Using flow cytomety, normal mice and mice possessing certain disorders lymphocyte development, the developmental stage that is affected by TCDD will be precisely determined. Analysis of cell cycle will determine whether TCDD causes an arrest in development or programmed cell death. Comparing alterations to cells exposed to TCDD in vivo and in vitro will assess the presence of any in vivo factors that may contribute to these responses, and determine if these cells are direct targets. Using fluorescent staining techniques and an in vivo AhR activation-reporter model, it will be determine whether AhR is present and transcriptionally active at affected stages of hemopoietic cell development. There are several candidate genes whose activities are critical at certain stages of lymphoid development. The activity of these genes will be examined at the cell stage shown to be affected. Finally, recent data has suggested a role of the AhR in the normal development of the immune system. Immune progenitor cells in animals lacking the AhR will be further characterized to determine this.